Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide

Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, 10032, USA.
Biological Psychiatry (Impact Factor: 10.25). 06/2004; 55(10):1001-6. DOI: 10.1016/j.biopsych.2004.01.018
Source: PubMed

ABSTRACT Previous imaging studies demonstrated that schizophrenia is associated with increased amphetamine-induced dopamine (DA) release in the striatum, most pronounced during episodes of illness exacerbation. Schizotypal personality disorder (SPD) is a schizophrenia spectrum disorder, genetically related to schizophrenia. The goal of this study was to investigate striatal DA function in patients with SPD.
In our study, 13 SPD patients and 13 matched healthy control subjects underwent single photon emission computed tomography (SPECT) scan during bolus plus constant infusion of the D2/3 radiotracer [123I]iodobenzamide (IBZM). Striatal specific to nonspecific equilibrium partition coefficient (V(3)") was measured at baseline and following amphetamine administration (.3 mg/kg).
No significant differences were observed in baseline V(3)" between groups. Amphetamine induced a larger decrease in [123I]IBZM V(3)" in SPD patients (-12 +/- 5%) compared with control subjects (-7 +/- 5%, p =.03).
The reduction in [123I]IBZM V(3)" induced by amphetamine in SPD was similar to that observed in remitted schizophrenia patients (-10 +/- 9%, n = 17), but significantly lower than that observed during illness exacerbation (-24 +/- 13%, n = 17). This suggests that DA dysregulation in schizophrenia spectrum disorders might have a trait component, present in remitted patients with schizophrenia and in SPD, and a state component, associated with psychotic exacerbations but not SPD.

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Available from: Lawrence S Kegeles, Jul 18, 2014
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    • "A recent single-photon emission computed tomography (SPECT) investigation revealed that the availability of striatal D2 receptors is associated with schizotypal features in healthy volunteers (Chen et al., 2012). Finally, another study in patients with schizotypal personality disorder (SPD) indicated exaggerated dopamine release in the striatum following d-amphetamine challenge (Abi-Dargham et al., 2004). However, more investigation of the function of brain networks is needed to map schizotypy in healthy individuals onto the Gaussian distribution of schizophrenia risk. "
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    ABSTRACT: "Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.
    Frontiers in Behavioral Neuroscience 07/2014; 8(235):eCollection2014. DOI:10.3389/fnbeh.2014.00235 · 4.16 Impact Factor
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    • "Patients with schizophrenia increase their baseline occupancy of D 2 receptors by DA and the availability of their D 2 receptors is higher than that of controls' D 2 receptors after DA depletion (Abi-Dargham et al., 2000). The hyperfunction of the striatal DA system has been previously suggested to be one of the key pathophysiological mechanisms in schizophrenic psychosis (Snyder, 1976; Davis et al., 1991; Abi-Dargham et al., 2004; Howes et al., 2009). Positive symptoms, which may be induced by the increase in synaptic DA concentration in the striatum (Breier et al., 1997; de Haan et al., 2004; Yang et al., 2004; Buchsbaum et al., 2006; Schmitt et al., 2008), play an important part in the diagnosis of schizophrenia. "
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    ABSTRACT: Individuals with schizotypal features exhibit cognitive, perceptual and social deficits that are similar to but less prominent than those seen in patients with schizophrenia. Dopaminergic hyperactivity in the striatum has been related to the positive symptoms of schizophrenia, and brain-imaging studies of dopamine uptake in the striatum are thought to be linked to the pathophysiological mechanisms underlying schizophrenia. The aim of this study was to investigate whether the increased availability of striatal dopamine (DA) D(2/3) receptors is related to elevated levels of schizotypal features in healthy individuals. The Schizotypal Personality Questionnaire (SPQ) was administered to 55 healthy volunteers. The availability of their striatal DA D(2/3) receptors was analysed using [(123)I] iodobenzamide single photon emission computed tomography (SPECT). Although the SPQ total scores showed no correlation with the availability of total (left and right) striatal DA D(2) receptors, the SPQ disorganised subscale scores were positively correlated with the availability of right striatal DA D(2/3) receptors. Our findings demonstrated that the availability of striatal DA D(2/3) receptors may be associated with schizotypal features in healthy volunteers.
    Psychiatry Research 03/2012; 201(3):218-21. DOI:10.1016/j.pscychresns.2011.07.003 · 2.68 Impact Factor
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    • "dopamine concentration and thereby decrease the availability of D 2/3 -binding sites in molecular imaging studies with the benzamide positron emission tomography (PET) ligand [ 11 C]raclopride (Kegeles et al., 2000) and with the analogous SPECT ligand ([ 123 I] iodobenzamide [ 123 I]IBZM) (Laruelle et al., 2000). Conversely, pharmacological depletion of dopamine with a-methyl-para-tyrosine (AMPT) increased the striatal binding of [ 123 I]IBZM (Abi-Dargham et al., 2004), whereas reserpine treatment increased [ 11 C]raclopride binding (Ginovart et al., 1997), reflecting reduced competition from dopamine. This competitive binding model has been used for studies of functional activation of dopamine transmission in human brain in a variety of pharmacological (Laruelle, 2000) and cognitive challenge paradigms (Koepp et al., 1998) and has yielded new insight into the pathophysiology of schizophrenia (Laruelle et al., 2003). "
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    ABSTRACT: Molecular imaging studies with benzamide radioligands can reveal competition from endogenous binding at D(2/3)-receptors in living brain. However, single photon emission computed tomography (SPECT) methods suffer from limited spatial resolution, and [(11)C]-labeled ligands are only available at positron emission tomography (PET) research sites with cyclotron-radiochemistry facilities, whereas [(18)F] can be transported, due to its longer physical half-life. Therefore, we endeavored to characterize the vulnerabilities of the benzamide antagonist [(18)F]desmethoxyfallypride (DMFP) and its high-affinity congener [(18)F]fallypride (FP) to competition from endogenous dopamine in living mouse brain. Groups of awake mice were pretreated with saline, amphetamine (10 mg/kg), or reserpine (5 mg/kg), followed by i.v. tracer injections. Mice were killed at 2.5-90 min (DMFP) or 2.5-180 min (FP) circulation times. Brains were dissected and regional radioactivity concentration measured by gamma counting. Other groups of mice were anesthetized for dynamic microPET recordings with DMFP or FP. Binding potentials (BP(ND)) were calculated using cerebellum as reference region. With 90-min circulation, DMFP BP(ND) in striatum was 2.4 by dissection and 2.2 by microPET, which showed a 62% decrease in response to amphetamine-evoked dopamine release and a 33% increase after reserpine-evoked dopamine depletion. With 120-min circulation, FP BP(ND) in striatum was 24.1 by dissection and 9.2 by microPET, which showed a 31% decrease in the amphetamine group, but no effect of reserpine. Dissection showed similar sensitivities for FP binding, but only a 29% amphetamine-evoked reduction for DMFP. Relative to gold standard ex vivo results, microPET estimates of DMFP BP(ND) were unbiased, whereas FP BP(ND) in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D(2/3)-receptors in striatum of living mice.
    Synapse 12/2009; 64(4):313-22. DOI:10.1002/syn.20730 · 2.43 Impact Factor
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